Dynein axonemal heavy chain 11 (DNAH11) is a protein that is encoded by the DNAH11 gene in humans. [5] [6] In mice, the protein is encoded by the Dnahc11 gene, the murine homolog to human DNAH11. [7] The protein was previously known as 'left-right' dynein (with the corresponding gene alias lrd) in mice and is particularly notable during embryogenesis for orientation of the eventual body plan. [8] [9]
This gene encodes a member of the dynein heavy chain family, DNAH11, a microtubule-dependent motor ATPase protein critical for processes involving ciliary movement. The gene DNAH11 has reported associations in a number of important physiological processes including the movement of respiratory cilia, sperm motility, and establishment of the adult body plan. [7] [10] [11] [12] A knockout model of this gene has not been reported.
The body plan is naturally asymmetrical, and the overall order is defined during embryonic gastrulation in mammals where the three germ layers (endoderm, mesoderm, and ectoderm) are established. At the beginnings of gastrulation, the primitive node serves as the organizer and has motile cilia on its surface. [13] [14] These cilia are responsible for directing increased amounts of nodal to the left side of the developing embryo, establishing asymmetry. [7] For this reason, proper expression of DNAH11 is critical for correct establishment and subsequent development of the asymmetrical body plan.
Mutations in this DNAH11 have been implicated in causing Primary Ciliary Dyskinesia (PCD), formerly called 'immotile cilia syndrome', and results from abnormally motile or static cilia within the respiratory tract. [7] PCD is characterized by bronchiectasis, frequent upper respiratory tract infections, and issues with fertility, and PCD individuals have increased rates of heterotaxy and situs inversus in approximately 50% of reported cases, a congenital condition in which some organs are mirrored to an abnormal side of the body cavity. [15] [16] Mutations in DNAH11 are also associated with Kartagener syndrome (PCD with situs inversus totalis, a congenital condition with a characteristic total inversion of the body plan and organs). [15]
Genetic errors with DNAH11 have been shown to cause a number of fertility-related effects in both sexes. Decreased motile cilia-specific expression of DNAH11 within the axoneme of sperm is associated with lower levels of sperm motility. [17] [18] For this reason, males with PCD are not sterile, but they are often infertile under conventional methods due to lack of sperm motility; [6] [18] however, there are cases of DNAH11 mutant males fathering offspring without intervention of assisted reproductive technologies. [19] [20] In females with PCD or Kartagener's syndrome, there are increased reports of subfertility and risk of ectopic pregnancy. [21] [22] Because females' fallopian tubes are lined with motile cilia which show identical motor protein composition to those observed in the respiratory tract, this is believed to result in the increased risks observed in case studies (although affected PCD females' cilia have not been directly analyzed so this remains inconclusive). [23]
The cilium is a membrane-bound organelle found on most types of eukaryotic cell. Cilia are absent in bacteria and archaea. The cilium has the shape of a slender threadlike projection that extends from the surface of the much larger cell body. Eukaryotic flagella found on sperm cells and many protozoans have a similar structure to motile cilia that enables swimming through liquids; they are longer than cilia and have a different undulating motion.
Situs inversus is a congenital condition in which the major visceral organs are reversed or mirrored from their normal positions. The normal arrangement of internal organs is known as situs solitus. Although cardiac problems are more common, many people with situs inversus have no medical symptoms or complications resulting from the condition, and until the advent of modern medicine, it was usually undiagnosed.
Primary ciliary dyskinesia (PCD) is a rare, autosomal recessive genetic ciliopathy, that causes defects in the action of cilia lining the upper and lower respiratory tract, sinuses, Eustachian tube, middle ear, fallopian tube, and flagella of sperm cells. The alternative name of "immotile ciliary syndrome" is no longer favored as the cilia do have movement, but are merely inefficient or unsynchronized. When accompanied by situs inversus the condition is known as Kartagener syndrome.
An axoneme, also called an axial filament is the microtubule-based cytoskeletal structure that forms the core of a cilium or flagellum. Cilia and flagella are found on many cells, organisms, and microorganisms, to provide motility. The axoneme serves as the "skeleton" of these organelles, both giving support to the structure and, in some cases, the ability to bend. Though distinctions of function and length may be made between cilia and flagella, the internal structure of the axoneme is common to both.
Dynein axonemal heavy chain 5 is a protein that in humans is encoded by the DNAH5 gene.
Dynein heavy chain 9, axonemal is a protein that in humans is encoded by the DNAH9 gene.
Dynein axonemal intermediate chain 1 is a protein that in humans is encoded by the DNAI1 gene.
A ciliopathy is any genetic disorder that affects the cellular cilia or the cilia anchoring structures, the basal bodies, or ciliary function. Primary cilia are important in guiding the process of development, so abnormal ciliary function while an embryo is developing can lead to a set of malformations that can occur regardless of the particular genetic problem. The similarity of the clinical features of these developmental disorders means that they form a recognizable cluster of syndromes, loosely attributed to abnormal ciliary function and hence called ciliopathies. Regardless of the actual genetic cause, it is clustering of a set of characteristic physiological features which define whether a syndrome is a ciliopathy.
Leucine-rich repeat-containing protein 50 is a protein that in humans is encoded by the LRRC50 gene.
Radial spoke head protein 4 homolog A, also known as radial spoke head-like protein 3, is a protein that in humans is encoded by the RSPH4A gene.
Dynein axonemal intermediate chain 2 also known as axonemal dynein intermediate chain 2, is a protein that in humans is encoded by the DNAI2 gene.
Thioredoxin domain-containing protein 3 (TXNDC3), also known as spermatid-specific thioredoxin-2 (Sptrx-2), is a protein that in humans is encoded by the NME8 gene on chromosome 7.
Dynein axonemal light chain 1, (LC1) is a protein that in humans is encoded by the DNAL1 gene.
Kintoun, is a protein that is encoded by the DNAAF2 gene.
Radial spoke head 1 homolog (RSPH1), also known as cancer/testis antigen 79 (CT79) or testis-specific gene A2 protein (TSGA2), is a protein that in humans is encoded by the RSPH1 gene.
Ciliogenesis is defined as the building of the cell's antenna or extracellular fluid mediation mechanism. It includes the assembly and disassembly of the cilia during the cell cycle. Cilia are important organelles of cells and are involved in numerous activities such as cell signaling, processing developmental signals, and directing the flow of fluids such as mucus over and around cells. Due to the importance of these cell processes, defects in ciliogenesis can lead to numerous human diseases related to non-functioning cilia. Ciliogenesis may also play a role in the development of left/right handedness in humans.
CCDC40 is the gene in humans that encodes the protein named coiled-coil domain containing 40.
Dynein axonemal heavy chain 1 is a protein that in humans is encoded by the DNAH1 gene.
Pleasantine Mill is a cell biologist and group leader at the MRC Human Genetics Unit at the University of Edinburgh. She won the 2018 British Society for Cell Biology Women in Cell Biology Early Career Medal.
Alfons Karlovich Siewert (1872–1922), also called Alfons Karlovich Zivert or Alfonse-Ferdinand-Julius-Zivert, was a Ukrainian physician, who hailed from a German family closely allied to the Tsar and Imperial Russia. He is known for his eponymous contribution to the Siewert-Kartagener syndrome.
